Septicemia is a serious world-wide health problem associated with mortality rates of 40-60%. It has been estimated that 1% of hospital patients and 20-30% of ICU patients develop sepsis. The cardiovascular consequences of septic shock resulting from bacterial infections include myocardial dysfunction that develops in nearly all patients, vascular tone and permeability abnormalities, as well as abnormal oxygen delivery and metabolism. As a result, vital organs such as the brain, heart, kidneys, and liver may be affected or may fail, and this reflects in over 100 000 deaths annually in the US. Septic shock is initiated by the introduction of a bacterial endotoxin (or lipopolysaccharide, LPS) into the blood stream. LPS (FIG. 1), a vital component of the outer leaflet of the gram-negative outer membrane, has been shown to be a principle mediator of the depression of left ventricular function and myocardial contractility.
LPS is comprised of three structural regions. One of these, the Lipid A region, consists of a polyacylated glucosamine disaccharide and is largely responsible for the toxic activity. The results of recent studies suggest that the ensuing proinflammatory response to LPS is by far more dangerous than the mere presence of LPS in circulation. LPS exerts its effects via interaction with a plasma LPS-binding protein (LBP), which has strong affinity for both the Lipid A region of the endotoxin and glycosylphosphatidyl inositol-anchored LPS receptor CD14 on mononuclear phagocytes. The LPS-LBP complex then interacts with CD14 followed by further complex formation with Toll-like receptor 4 (TLR4) and its co-receptor MD-2. TLR4 is an integral membrane protein that transmits the LPS signal to the inside of the cell and initiates the signaling pathways that lead to production of proinflammatory molecules, such as the cytokine, tumor necrosis factor α (TNFα).
Recent advances in the understanding of LPS structure-function relationships have provided some clues on the structural determinants responsible for the endotoxic activity of Lipid A. These determinants include the number and chain length of fatty acids (lipids), the disaccharide core, and the 1,4′-diphosphate groups of the E. coli type (1, FIG. 1). The fair stability (chemical or in vitro) of this class of compounds has been a major drawback in their synthesis and application. Although the exact role of the phosphate moieties is still unknown, the observation that a 1-hydroxyl-4′-O-phosphate derivative was inactive gave rise to a belief that the omission of at least one phosphate results in a complete loss of activity (Rossignol et al., Endotoxin in Health and Disease, eds. Brade, Opal, Vogel and Morrison, Marcel Dekker, Inc., New York—Basel, 1999, pp. 699-717; Christ et al., J. Am. Chem. Soc., 1994, 116, 3637-3634).
Accordingly, there is a need for compounds that antagonize LPS signaling without activating the inflammatory cascade. There is also a need for Lipid A analogs that lack the complexity of the highly lipidated diphosphorylated disaccharide core yet still maintain potent antagonistic activity against LPS.